The overall objective of this project is to overcome the resistance to nucleoside antimetabolites by finding a way to introduce the nucleotide into the cells. It is assumed that phosphotriesters of intermediary stability would be suitable to achieve this goal. We are synthesizing and testing trinucleoside monophosphates containing FUdR. Most of our activity centers on triesters of cyclic AMP, some of which were recently shown to be cytotoxic in vitro and also active in vivo. The chemical technology has yet to be worked out for the improved production of methyl, ethyl, propyl, butyl, cyanoethyl and phenyl esters of cyclic AMP. Biochemical studies of these triesters are aimed at the demonstration of their being suitable storage forms of cyclic AMP. Activation of phosphorylase of liver in vitro and in vivo, and lypolysis will be studied. Biological studies involve testing in hepatomas, Ehrlich ascites, and Walker 256 systems. Attempts will also continue to obtain triesterified oligonucleotides (polypyrimidines).